Peripheral arterial disease (PAD) is characterized by arterial obstruction due to atherosclerosis that impairs blood flow to the lower limb and is common; affecting over 8 million individuals in the U.S. Presently used noninvasive imaging methods have limitations as endpoints for clinical trials of novel therapies in PAD. Over the past 8 years, our multi-disciplinary team has developed new magnetic resonance imaging (MRI) measures to study PAD. We have established phosphocreatine (PCr) recovery kinetics after exercise by 31P spectroscopy (MRS) as a reliable and reproducible marker of PAD. Using contrast enhanced MR (CE-MRI) at peak exercise; calf muscle perfusion can be assessed. With arterial spin labeling (ASL) MRI, a non-contrast technique, peak calf perfusion can be measured on a ml/min/100g basis and test-retest reliability is excellent. We hypothesize that a new and improved approach to ASL to measure blood flow kinetics and improved absolute quantification with CE-MRI will both have the sensitivity to detect significant changes in calf muscle perfusion. Specific Aim #1 is to optimize MRI methods to fully quantify skeletal muscle blood flow and flow kinetics at peak exercise with or without a contrast agent in PAD. Cuff occlusion/hyperemia as a means of increasing blood flow may be best suited to those who can't exercise and may be more reproducible than exercise. Thus, Specific Aim #2 is to compare stressors for optimal measurement of peak calf muscle blood flow: cuff occlusion/hyperemia versus exercise. Normal subjects and patients with PAD will undergo both approaches to increase blood flow. Test-retest studies of reproducibility will be compared between techniques. Best protocols will be chosen for studies in Aim 3. We hypothesize that our novel and improved methods may be able to detect more subtle changes in perfusion and metabolism made possible by therapies such as exercise. Specific Aim #3 is to test the ability to detect improved calf muscle perfusion and energetics in PAD patients in a randomized controlled trial of home exercise therapy. Eighty patients will be randomized to a 12 week home exercise program or no program (control). Patients will be studied before and after program completion with MRI/MRS, calf muscle biopsy for capillary density, and exercise performance measures. Optimized ASL and quantitative CE-MRI will be used based on Aims 1 and 2, one in each leg. The method of stress for measurement of perfusion will be the most reproducible from Aim 2. All will undergo ASL and CE-MRI (except those with severe chronic kidney disease), peak exercise PCr recovery kinetics, calf muscle biopsy, and functional measures including treadmill exercise, VO2 testing, and 6-minute walk. Correlations will be examined between changes in perfusion and energetics with changes in capillary density, peak VO2, and functional capacity from before to after completion of home exercise therapy. We expect to find that improvements in perfusion and energetics will correlate with these latter measures and thus will be useful and unique markers of response to novel therapeutics in PAD. PUBLIC HEALTH RELEVANCE: Peripheral arterial disease (PAD) affects over 8 million in the U.S. and techniques to evaluate potential benefits of new treatments are sorely lacking. This study aims to further develop and test new techniques using magnetic resonance imaging. We will test the utility of these new techniques on patients with PAD before and after home exercise therapy to determine mechanisms of benefits of exercise.